A Phase I Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) With Dose Expansion Cohorts in Patients With Advanced Solid Tumors

Phase I with a dose finding cohort, followed by expansion cohorts in pre-specified tumor types.

开始日期2025-01-20

申办/合作机构

Institut Curie

[+2]

NCT06518564

/ Recruiting临床2期IIT

A Phase 2 Study of Avelumab in Combination With ATR Inhibitor M1774 in Patients With ARID1A-mutated Recurrent Endometrial Cancer Who Have Received Prior Immunotherapy

The purpose of this research study is to see if the combination of study drugs avelumab and M1774 is effective and safe for participants with endometrial cancer.
The names of the study drugs involved in this study are:
* Avelumab (a type of human IgG1 antibody)
* M1774 (a type of ATR inhibitor)

开始日期2024-11-14

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+1]

NCT06433219

/ Active, not recruiting临床2期

An Open-label, Multicenter, Randomized Phase 2 Study of the ATR Inhibitor Tuvusertib in Combination With the PARP Inhibitor Niraparib or the ATM Inhibitor Lartesertib in Participants With BRCA Mutant and/or Homologous Recombination deﬁciency (HRD)-Positive Epithelial Ovarian Cancer That Progressed on Prior PARP Inhibitor Therapy (DDRiver EOC 302)

The purpose of this study is to measure the effect and safety of treatment with tuvusertib combined with either niraparib or lartesertib in participants with epithelial ovarian cancer and to assess any differences between tuvusertib monotherapy and combination therapy. The participants will previously have progressed while treated with a poly ADP ribose polymerase (PARP) inhibitor. The primary objectives of this study are to assess the effect of the treatment in terms of overall response, i.e. whether the tumor disappears, shrinks, remains unchanged, or gets worse and safety in terms of adverse events.

开始日期2024-10-30

申办/合作机构

EMD Serono Research & Development Institute, Inc.

[+1]

100 项与 Tuvusertib 相关的临床结果

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100 项与 Tuvusertib 相关的转化医学

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100 项与 Tuvusertib 相关的专利（医药）

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项与 Tuvusertib 相关的文献（医药）

2025-07-01·BIOMEDICAL CHROMATOGRAPHY

Quantitation of Tuvusertib (M1774) in Human Plasma by LC‐MS/MS

Article

作者: Holleran, Julianne L. ; Le, Tien V. ; Beumer, Jan H. ; Bakkenist, Christopher J. ; Feng, Ye ; Cote, Gregory M. ; Parise, Robert A. ; Gore, Steven D. ; Synold, Timothy

ABSTRACT:

Ataxia‐telangiectasia and Rad3‐related (ATR) protein kinase is an essential regulator of the DNA damage response (DDR) at stalled and collapsed replication forks. Tuvusertib (M1774) is a selective, orally available small molecule ATR inhibitor currently in preclinical and clinical development for cancer treatment. This study presents a robust and simple 5‐min assay designed for the quantification of single agent tuvusertib in human plasma utilizing liquid chromatography tandem mass spectrometry (LC‐MS/MS). A 20 μL volume of plasma was subjected to protein precipitation, followed by chromatographic separation using a Phenomenex Synergi Polar‐RP (4 μm, 2.1 × 50 mm) and a gradient mobile phase system consisting of 0.1% formic acid in both water and acetonitrile during a 4‐min run time. Mass spectrometric detection was achieved using a SCIEX 6500+ tandem mass spectrometer with electrospray positive‐mode ionization. With a stable isotopic internal standard, our assay met the criteria outlined by the Food and Drug Administration guidance for bioanalytical method validation, demonstrating robust performance within the range from 5 to 5000 ng/mL. This assay will support ongoing and future clinical studies by defining tuvusertib pharmacokinetics.

2024-12-01·BRITISH JOURNAL OF HAEMATOLOGY

Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3‐dependent mechanism in vitro and in vivo

Article

作者: Canevarolo, Rafael R. ; Kmieciak, Maciej ; Shain, Kenneth H. ; Meads, Mark B. ; Grant, Steven ; Nkwocha, Jewel ; Li, Lin ; Silva, Ariosto S. ; Hu, Xiaoyan ; Alugubelli, Raghunandan R. ; Zhou, Liang ; Sudalagunta, Praneeth R. ; Mann, Hashim

Summary:

Mechanisms underlying potentiation of the anti‐myeloma (MM) activity of ataxia telangiectasia Rad3 (ATR) antagonists by MAPK (Mitogen‐activated protein kinases)‐related extracellular kinase 1/2 (MEK1/2) inhibitors were investigated. Co‐administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines. Mechanistically, BAY and cobimetinib blocked STAT3 Tyr705 and Ser727 phosphorylation, respectively, and dual dephosphorylation triggered marked STAT3 inactivation and downregulation of STAT3 (Signal transducer and activator of transcription 3) downstream targets (c‐Myc and BCL‐X L ). Similar events occurred in highly bortezomib‐resistant (PS‐R) cells, in the presence of patient‐derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors. Notably, constitutively active STAT3 c‐MYC or BCL‐X L ectopic expression significantly protected cells from BAY/cobimetinib. In contrast, transfection of cells with a dominant‐negative form of STAT3 (Y705F) sensitized cells to cobimetinib, as did ATR shRNA knockdown. Conversely, MEK1/2 knockdown markedly increased ATRi sensitivity. The BAY/cobimetinib regimen was also active against primary CD138 + MM cells, but not normal CD34 + cells. Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib‐resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.

2024-10-01·CTS-Clinical and Translational Science

Asia‐inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler

Review

作者: Kuroki, Yoshihiro ; Venkatakrishnan, Karthik ; Bolleddula, Jayaprakasam ; Dong, Jennifer ; Strotmann, Rainer ; Lu, Hong ; Klopp‐Schulze, Lena ; Mukker, Jatinder Kaur ; Gao, Wei ; Terranova, Nadia ; Li, Dandan ; Goteti, Kosalaram

Abstract:

With the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia‐inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model‐informed Asia‐inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3‐related inhibitors, tuvusertib and berzosertib (oncology), the toll‐like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model‐informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia‐inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de‐risking ethnic sensitivity to inter‐population variations in drug‐ and disease‐related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.

项与 Tuvusertib 相关的新闻（医药）

2025-11-14

·博药

DDR赛道第二波：为何全球药企都在押注ATR？

在肿瘤治疗的靶向疗法浪潮中，DNA损伤应答（DDR）通路曾凭借PARP抑制剂的成功引领了黄金十年。从奥拉帕利获批上市至今，PARP抑制剂已在卵巢癌、乳腺癌等多个实体瘤领域确立了标准治疗地位，为携带BRCA突变的患者带来显著生存获益。但随着临床应用的深入，原发性耐药与获得性耐药问题逐渐凸显，约40%-60%的患者在治疗后会出现疾病进展，这成为制约PARP抑制剂临床价值的关键瓶颈。因此，耐药困境下的行业开始将目光投向DDR通路更上游的核心调控分子——ATR（Ataxia Telangiectasia and Rad3-related，共济失调-毛细血管扩张和Rad3-相关激酶）。其作为复制应激应答的"总开关"，在维持基因组稳定性中发挥不可替代的作用。如今，从AZ到默克，从恒瑞医药到正大天晴，小分子ATR抑制剂正被视为“PARP之后的DDR新星”，已然成为全球研发布局的重点方向。 ATR的机制逻辑：复制应激中的肿瘤脆弱点突破 DNA损伤应答（DNA Damage Response，DDR）作为细胞维持基因组稳定性的核心防御体系，主要包括碱基切除修复（BER）通路和同源重组（HR）/非同源末端连接（NHEJ）通路。而通常情况下，DNA修复的过程往往发生在损伤位点附近的染色质区域，其过程非常复杂，且伴随多种肿瘤发生，因此相关蛋白也是重要的潜在的药物靶点。其中，PARP是单链断裂修复的关键分子，也是首个在临床验证的DDR靶点。其抑制剂通过阻断BER通路，使DNA单链损伤无法修复并转化为双链断裂，在HR缺陷（如BRCA突变）的肿瘤细胞中诱发“合成致死”，成功掀起了DDR靶向治疗的第一波浪潮。图1：DNA修复通路中主要传感器、信号传导和效应蛋白（点击查看大图）图注：蓝色阴影区域表示双链断裂（DSB）修复通路；红色阴影区域表示单链断裂（SSB）修复通路，其中药物开发的主要靶点以红色标注[1] 而在复制应激及双链断裂修复环节中，ATR是DDR核心的关键激酶，负责感知复制应激（Replication Stress，RS）并将其信号传递至S和G2/M期检查点以启动DNA修复。ATR与DNA依赖性蛋白激酶催化亚基（DNA-PKcs），共济失调毛细血管扩张突变基因（ATM基因）构成了DDR的三大核心激酶。而上述三者虽同属PIKK家族，其分工却有所不同：ATM与DNA-PKcs主要感应和修复双链断裂，而ATR则专责应对复制应激（Replication Stress, RS）——这是癌细胞在高速分裂、基因组不稳定背景下产生的核心脆弱点。ATR通过感知RS，启动CHK1等下游信号，参与DNA单链断裂修复，维持复制稳定性并防止细胞崩溃[2]。图2：ATR的生物学功能[2]（点击查看大图）值得一提的是，ATM基因不是细胞存活必需的，人类ATM基因的突变会导致共济失调毛细血管扩张症的发生，其特点是小脑退化、免疫缺陷和癌症风险增加。但ATR是至关重要的，有研究表明ATR双等位基因的丧失会导致早期胚胎致死。因此，ATR的选择性抑制为肿瘤治疗提供了新的思路，也为肿瘤研究提供了新的工具，目前，ATR抑制剂（ATRi）主要是通过两条途径进行临床应用开发。第一条：寻找预测性生物标志物来识别对单药治疗特别敏感的肿瘤该途径是通过寻找预测性生物标志物（如ARID1A、ATM）来识别对单药治疗特别敏感的肿瘤。管线代表有：Berzosertib（M6620/VE822）、Ceralasertib（AZD6738）、Elimusertib（BAY1895344）、M1774和RP-3500(Camonsertib）。其中，阿斯利康的Ceralasertib在Ⅱ期临床研究的初步结果表明，在ARID1A缺乏实体瘤患者中，Ceralasertib单药显示出具有良好的抗肿瘤活性（160mg，1日2次，口服d1～14，28d为1个周期），客观缓解率（ORR）为20%，观察到2例完全缓解（CR），这两例患者仍在接受治疗，持续缓解时间分别为19.8+个月和14.7+个月，且完全缓解状态仍在持续。另有1例患者因疾病稳定（SD）持续治疗8.8个月，Ceralasertib单药的总体临床获益率（缓解或疾病稳定持续＞6个月）为30%[4]。图3：ATR抑制剂敏感的潜在生物标志物[2]（点击查看大图）第二条：探索与其他药物联合用药的策略 ① 与化疗联合例如吉西他滨（Gemcitabine），吉西他滨联合Berzosertib组的中位无进展生存期为22.9周（90%CI 17.9-72.0），而吉西他滨单独使用组的中位无进展生存期为14.7周（9.7-36.7）（HR 0.57,0.33-0.98；单侧对数秩检验p=0.044；上单侧90%CI 0.87 [5]；此外还有铂化合物[6-7]、拓扑替康类[8-9]等等。图4：吉西他滨联合Berzosertib治疗铂类耐药高级别浆液性卵巢癌[5]（点击查看大图） ② 与PARP抑制剂（PARPi）联合一些临床前研究表明，PARPi与ATRi在卵巢癌患者中具有协同作用。这种协同作用存在于野生型和BRCA1、BRCA2突变的肿瘤中，但在野生型肿瘤中更明显。ATR抑制可能是克服PARPi耐药性的关键机制，包括恢复HRR缺乏、复制叉稳定、SLFN11失活和PARG表达缺失，其分子机制可能是pATR和pCHK1水平降低，RAD51募集减少，pH2AX积累增加。图5：PARPi–ATRi处理能显著降低肿瘤细胞活力[10]（点击查看大图）同时，一项CAPRI试验评估了Ceralasertib联合Olaparib对铂类敏感并经过至少6个月的PARPi治疗后进展的卵巢癌患者的疗效，在13例患者中6例患者达到部分缓解，ORR为46%[11]。 ③ 与免疫疗法联合一项Ⅱ期试验评估了Ceralasertib联合Durvalumab治疗既往PD-1治疗失败的晚期/转移性黑色素瘤患者，结果显示ORR为30%，30例患者mPFS为7.1个月（95%CI，3.6-10.6个月）；在数据截止时，30例患者中有14例死亡，中位OS为14.2个月（95%CI，9.3-19.1个月）[12]。图6：Ceralasertib联合Durvalumab治疗黑色素瘤患者结果图[12]（点击查看大图）综上所述，ATR抑制剂在肿瘤治疗上之所以能拥有如今地位，其两大核心亮点功不可没，一者是特异性杀伤，原则上仅在DNA修复缺陷（如ATM缺失）或高复制应激的肿瘤细胞中发挥毒性，对正常细胞损伤极小；二者是逆转肿瘤耐药性，研究数据证明，ATR抑制剂铂类化疗耐药和PARP抑制剂耐药的肿瘤拥有显著活性，尤其是KRAS+STK11/LKB1+KEAP1三突变，也可逆转免疫治疗耐药，重建抗肿瘤免疫。目前，ATR已成为当前DDR靶点中最具系统性扩展潜力的方向之一，覆盖小细胞肺癌、三阴性乳腺癌、卵巢癌、胃癌/食管癌等多种常见肿瘤类型。全球研发格局：巨头领跑，20款候选药角逐临床截至2025年，全球已有约20个ATR抑制剂进入临床阶段（表1，仅统计活跃管线，近三年有研发进展），其中以阿斯利康的Ceralasertib进展最快，目前已经进展至临床Ⅲ期，其次是默克的Berzosertib和Tuvusertib，目前均处于临床Ⅱ期。表1 全球ATR靶点药物研发进展数据来源：药智全球药物研发系统（点击查看大图，如有错误请指正）具体来看，阿斯利康开发的高选择性ATR抑制剂，即Ceralasertib（AZD6738）研发重点聚焦于复制应激高（RS-high）或DNA修复缺陷（如ATM缺失、HRD）肿瘤，在与PD-L1抑制剂Durvalumab、PARP抑制剂及化疗/放疗联合时表现出良好的耐受性和初步疗效。多项研究显示，ATM变异患者获益显著，验证了其“合成致死”作用机制。当前，Ceralasertib被视为继PARP抑制剂之后DDR领域最具潜力的下一代靶点药物，有望在精准分型和联合治疗策略中拓宽抗癌新路径。表2 Ceralasertib临床试验汇总时间表数据来源：公开资料整理（点击查看大图，如有错误请指正）默克Berzosertib（M6620） Berzosertib早期联合化疗显示出较好的肿瘤缩小率，被认为是首批“可临床证明概念”的ATR抑制剂之一。在单药治疗晚期实体瘤患者疗效的I期临床试验结果ORR为19%（4/21），所有4例患者均同时携带ATM的缺失或变异，但其中81.8%的患者出现ATRi的常见不良反应3级贫血，提示1例携带BRCA1致病突变，并对PARPi耐药的患者得到了长期缓解[13]。而关键临床Ⅱ期试验数据显示，在2023年1月27日的数据截止时（从初步分析开始>额外随访30个月），吉西他滨/贝佐塞替布组的中位OS为59.4周，而吉西他滨单用组为43.0周（HR 0.79，90%CI 0.52-1.2，单侧对数秩P=.18）。展现出吉西他滨/ATRi联合治疗铂类耐药卵巢癌的前景[14]。表3 Berzosertib临床试验汇总时间表数据来源：公开资料整理（点击查看大图，如有错误请指正）两者对比来看，Ceralasertib是小分子口服ATR抑制剂，高选择性抑制ATR-CHK1通路以阻断复制应激修复，对ATM缺陷肿瘤、HRD阳性肿瘤选择性更强，更易与PD-1/PD-L1、PARP抑制剂联用，能有效突破PARP抑制剂耐药困境，且产业链完善、研发进展领先；而Berzosertib是靶向ATR的静脉注射小分子抑制剂，通过抑制ATR激酶活性诱导复制叉崩溃和细胞死亡，对复制应激显著升高的肿瘤敏感度更高，主要与吉西他滨、顺铂等化疗药物联用，虽早期开发领先，但后期推进稍慢。项目 Ceralasertib(AZD6738) Berzosertib(M6620/VX-970) 开发公司阿斯利康默克分子类型小分子口服ATR抑制剂靶向ATR的静脉注射小分子抑制剂作用机制高选择性抑制ATR-CHK1通路，阻断复制应激修复抑制ATR激酶活性，诱导复制叉崩溃和细胞死亡选择性特点对ATM缺陷肿瘤、HRD阳性肿瘤选择性更强对复制应激显著升高的肿瘤敏感度更高联合潜力更易与PD-1/PD-L1、PARP抑制剂联用主要与化疗（如吉西他滨、顺铂等）联用耐药机制突破对PARP抑制剂耐药肿瘤有效，可作为“PARPi后接力” 联合化疗时可增强DNA损伤积累商业化前景产业链完善，进展领先早期开发领先，但后期推进稍慢数据来源：公开数据整理其他产品例如罗氏的RP-3500（Camonsertib）在具有DDR基因变异的实体瘤患者中的Ⅰ/Ⅱ期临床试验结果显示在卵巢癌患者中ORR为25%（5/20），其中17例为铂类耐药，18例曾接受过PARPi治疗，也具备较高的潜力。从整体研发趋势看，ATR正从“验证疗效”转向“优化耐受性+靶向精准化”的第二阶段。中国进展：从跟随到同步近年来，国内药企在DDR领域的布局明显加快。药智数据显示，已有超过7个ATR抑制剂项目在研，其中不乏领军企业：恒瑞医药（HRS-2398）：HRS2398缓释片是一款新型、高效、口服的ATR抑制剂，能够有效抑制ATR激酶活性，加剧DNA双链损伤，抑制细胞增殖，发挥抗肿瘤作用。2024年4月HRS2398国内获批临床，拟用于治疗晚期恶性肿瘤患者。目前全球最高阶段为临床Ⅱ期，中国最高阶段为临床Ⅰ期。图片来源：CDE官网（点击查看大图）中国生物制药（TCC1727）：临床前研究显示，TCC1727单药表现出较好的安全性和疗效，与化疗药和PAPR抑制剂等药物联合时表现为协同抗增殖的作用。目前正在开展TCC1727联合贝莫苏拜单抗/奥拉帕利/托泊替康治疗晚期实体瘤的开放性、多中心Ⅰb/Ⅱ期临床试验。正大天晴（TQB-3015）：2023年11月已获CDE批准开展药物临床试验，拟用于治疗晚期恶性肿瘤，目前正在临床I期。智康弘仁（SC0245）：国内较早开始单臂、开放性、多中心的Ib/Ⅱ期临床试验的ATR抑制剂，SC0245口服片剂（ATRi）联合盐酸伊立替康注射液（TOP1i）治疗，研究病例多中心/Ib剂量递增约3-27例，Ib剂量扩展约10例，Ⅱ期30例正在开展中（CTR20223363）。相较PARP的仿制潮，国内ATR方向目前仍处于原创窗口期，中国研发力量有机会跟上国际节奏，实现同频发展。结语从PARP抑制剂开创的DDR靶向治疗黄金时代，到ATR抑制剂扛起破解耐药、拓展治疗边界的大旗，肿瘤精准治疗正迈入“合成致死2.0时代”。ATR作为复制应激应答的核心开关，凭借“特异性杀伤DNA修复缺陷肿瘤+逆转多线治疗耐药”的双重优势，以及与化疗、PARP抑制剂、免疫治疗的广泛协同潜力，已成为全球药企竞逐的核心靶点。当前，阿斯利康、默克等巨头的Ⅲ期临床已进入关键冲刺阶段，2026-2027年有望迎来首款ATR抑制剂获批，届时将为铂类耐药卵巢癌、三阴性乳腺癌等难治性肿瘤患者带来全新治疗选择，更将重塑DDR赛道的市场格局。而中国药企在这一波浪潮中并未缺席，恒瑞医药、中国生物制药、正大天晴等企业的原创管线已进入临床阶段，凭借“同步国际研发节奏+差异化联合策略”，正从“跟跑者”向“并行者”突围。更关键的是，相较于PARP抑制剂领域的仿制扎堆，ATR赛道目前仍处于原创窗口期，国内企业有望借助对中国患者生物标志物特征的深刻理解、灵活的临床开发策略，在特定适应症或联合疗法中实现弯道超车。未来，随着Ⅲ期临床数据的披露、生物标志物的精准落地以及联合治疗方案的优化，ATR抑制剂不仅将填补PARP耐药后的治疗空白，更可能与现有疗法形成协同网络，构建覆盖肿瘤全病程的精准治疗体系。对于全球医药行业而言，ATR的崛起标志着DDR赛道从“单点突破”走向“通路全面布局”；对于中国创新药而言，这既是参与全球竞争的挑战，更是凭借原创实力占据赛道核心地位的历史性机遇。这场围绕ATR的研发角逐，终将为肿瘤患者带来更多生存希望，也将见证中国创新药在全球精准治疗领域的全新突破。参考文献 1.Brown JS, et al. Targeting DNA Repair in Cancer: Beyond PARP Inhibitors. Cancer Discov. 2017 Jan;7(1):20-37. doi: 10.1158/2159-8290. 2.Ngoi NYL, et al. Targeting ATR in patients with cancer. Nat Rev Clin Oncol. 2024 Apr;21(4):278-293. doi: 10.1038/s41571-024-00863-5. 3.刘竹君, 刘东颖. ATR抑制剂抗肿瘤治疗的研究新进展[J]. 中国肿瘤临床, 2023, 50(15): 791-796. doi: 10.12354/j.issn.1000-8179.2023.20230644 4.Aggarwal R, Umetsu S, Dhawan M, et al. 512O Interim results from a phase Ⅱ study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies[J]. Ann Oncol, 2021, 32:S583. 5.Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(7):957-968. 6.Yap TA, et al. Phase Ⅰ trial of first-in class ATR inhibitor M6620 (VX-970) as monotherapy or in combin ation with carboplatin in patients with advanced solid tumors[J]. J Clin Oncol, 2020, 38(27):3195-3204. 7.Yap TA, et al. Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study. Clin Cancer Res. 2021 Oct 1;27(19):5213-5224. 8.Thomas A, et al. Phase Ⅰ study of ATR inhibit or M6620 in combination with topotecan in patients with ad vanced solid tumors[J]. J Clin Oncol, 2018, 36(16):1594-1602. 9.Thomas A, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress[J]. Cancer Cell, 2021, 39(4):566-579. 10.Kim, H., et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 11, 3726 (2020). 11.Wethington SL, et al. Combination ATR (ceralasertib) and PARP (olaparib) inhibitor (CAPRI) trial in acquired PARP inhibitor-resistant homologous recombination-deficient ovarian cancer[J]. Clin Cancer Res, 2023, 29(15):2800-2807. 12.Kim R, et al. Phase Ⅱ study of ceralasertib (AZD6738) in combination with durvalumab inpatients with ad vanced/metastatic melanoma who have failed prior anti-PD-1 therapy[J]. Ann Oncol, 2022, 33(2):193-203. 13.Yap TA, et al. First-in-human trial of the oral Ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors[J]. Cancer Discov, 2021, 11(1):80-91. 14.Konstantinopoulos PA, et al. Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses. JCO Precis Oncol. 2024 Apr;8:e2300635. doi: 10.1200/PO.23.00635. 博腾股份成立于2005年，主要为全球药企、生物科技公司、科研机构等提供从临床前研究到药品上市全生命周期所需的小分子药物、多肽与寡核苷酸药物、蛋白与偶联药物以及细胞与基因治疗药物等一站式服务解决方案，研发、生产、运营场地覆盖中国（重庆、上海、四川、江苏、江西、湖北）、美国、斯洛文尼亚、比利时、瑞士和丹麦等地。我们始终坚持以客户为中心，致力于为客户提供创新、可靠的全球化、端到端CDMO服务，让好药更早惠及大众。免责声明：本文仅作者个人观点的表达，文中观点不代表博腾及其所属子公司立场，亦不对本文所提供信息做任何形式的保证。同时，本文不做治疗方案推荐，也不承担因使用或依赖本文信息所产生的任何直接或间接的后果。如需获得治疗方案指导，请前往正规医院就诊。

上市批准临床结果

2025-06-14

·医药观澜

16款1类新药首次在中国获批临床！来自辉瑞、德国默克、乐普生物等

根据中国国家药监局药品审评中心（CDE）官网以及公开资料梳理，本周（6月9日~6月14日），有16款1类创新药首次在中国获得临床试验默示许可（IND）。这些产品涵盖了抗体偶联药物（ADC）、小分子药物、抗体药物等类型，拟定适应症涵盖癌症、罕见病、肾脏疾病等等。图片来源：123RF辉瑞（Pfizer）：PF-07985045片作用机制：小分子KRAS抑制剂适应症：携带KRAS突变的晚期实体瘤辉瑞申报的1类新药PF-07985045片获批临床，拟开发治疗携带KRAS突变的晚期实体瘤。根据辉瑞公开资料介绍，这是一款新一代小分子KRAS抑制剂类药物。辉瑞目前正在美国、日本等国家开展1期临床研究，评估PF-07985045片单独或与其他抗癌疗法一起用于KRAS突变的晚期实体瘤患者，包括非小细胞肺癌、结直肠癌、胰腺癌等。argenx：empasiprubart注射用浓溶液作用机制：补体C2抑制剂适应症：成人多灶性运动神经病（MMN）argenx公司申报的1类新药empasiprubart注射用浓溶液获批临床，拟开发治疗成人多灶性运动神经病（MMN）。公开资料显示，Empasiprubart (ARGX-117)被设计为一款人源化“清除抗体”（sweeping antibodies），以pH-和Ca2+依赖的方式特异性结合C2。C2是补体级联中的一种蛋白质，empasiprubart旨在抑制C2和下游补体激活的功能，从而减少组织炎症和适应性免疫反应。在国际范围内，该产品针对成人多灶性运动神经病适应症正处于3期临床研究阶段。该抗体的设计旨在增强抗体与内体中FcRn的结合，防止抗体进入溶酶体降解。良远生物医药：注射用人白介素-2（高亲和型复合物）作用机制：白介素-2适应症：晚期实体瘤良远生物医药申报的1类新药注射用人白介素-2（高亲和型复合物，研发代号LYC001）获批临床，拟开发治疗晚期实体瘤。公开资料显示，这是一款采用高亲和层级组装（High Affinity Hierarchical Assembly）技术平台研发的针对多种实体肿瘤的全新药物，该平台旨在通过淋巴系统给药的药物递送技术，解决现有大分子药物通过血液循环进行分布而导致的稳定性低、特异性差等问题，能够显著提高白介素-2的溶解度和稳定性。该产品以淋巴系统为靶标，皮下给药后由组织淋巴管收集，经逐级淋巴结和各级淋巴管后汇集于淋巴总管进入血液循环（生物利用度大于90%）。Tempest Therapeutics：TPST-1120片作用机制：小分子PPAR⍺拮抗剂适应症：肝细胞癌Tempest Therapeutics公司申报的1类新药TPST-1120片获批临床，拟用于既往未接受过系统性治疗的不可切除或转移性肝细胞癌患者。公开资料显示，这是一款口服、选择性小分子PPAR⍺拮抗剂。该产品可直接杀死肿瘤细胞，并靶向肿瘤微环境中的抑制性免疫通路。这两种类型中的靶向细胞皆依赖脂肪酸代谢，该代谢过程由PPARα转录因子调节。赛诺哈勃药业、倍特药业：SNH-119014片作用机制：小分子丙酮酸激酶激动剂适应症：血红蛋白病倍特药业及旗下赛诺哈勃药业申报的1类新药SNH-119014片获批临床，拟开发治疗血红蛋白病 (包括但不限于地中海贫血及镰状细胞病)。公开资料显示，这是赛诺哈勃药业研发的一款全新小分子丙酮酸激酶激动剂，该产品可明显提高丙酮酸激酶活性，增加生物标志物腺嘌呤核苷三磷酸（ATP）水平、降低2,3-二磷酸甘油酸（2,3-DPG）含量，满足患者红细胞的能量代谢需求，有望改善贫血、提高患者生活质量。礼新医药：LM-168注射液作用机制：抗CTLA-4抗体适应症：晚期实体瘤礼新医药申报的1类新药LM-168注射液获批临床，拟开发治疗晚期实体瘤。公开资料显示，LM-168是一款抗CTLA-4抗体。该产品经过工程化改造，可在肿瘤微环境（TME）中高ATP/ADP/AMP（ANP）水平下选择性结合CTLA-4，而在健康组织中结合力较弱，从而降低“脱靶毒性”。根据2025年AACR大会公布的研究结果，通过条件性靶向CTLA-4，LM-168旨在解决现有抗CTLA-4抗体面临的效价与耐受性挑战，有望成为兼具临床疗效与低毒性的下一代CTLA-4靶向疗法。此外，该药物预计可与抗PD-1/PD-L1疗法产生协同效应。乐普生物：MRG007作用机制：靶向CDH17的ADC适应症：局部晚期或转移性实体瘤乐普生物1类新药MRG007获批临床，拟开发治疗局部晚期或转移性实体瘤。公开资料显示，这是一款靶向CDH17的抗体偶联药物（ADC），由新型人源化IgG1抗体通过定点偶联细胞毒素Exatecan而成。今年1月，ArriVent BioPharma以一项超12亿美元合作获得该产品在大中华区以外地区开发、制造和商业化的全球独家许可。根据研究人员在今年AACR年会上公布的研究结果，MRG007具有平衡的药物抗体比（DAR），差异化设计有望提升抗肿瘤疗效并拓宽治疗窗。金赛药业：GenSci134注射液作用机制：生物制品1类新药适应症：成人生长激素缺乏症金赛药业申报的1类新药GenSci134注射液获批临床，拟开发治疗成人生长激素缺乏症。根据长春高新公告介绍，这是一款治疗用生物制品1类药物。生长激素缺乏症可在一生中各个阶段发生。成人生长激素缺乏常合并多种并发症，带来诸多危害，且患者可能需要长期甚至终身替代治疗，存在未被满足的临床需求。德国默克：lartesertib片剂、tuvusertib胶囊/片剂作用机制：ATM抑制剂、ATR抑制剂适应症：卵巢上皮癌德国默克（Merck KGaA）申报的lartesertib片剂和tuvusertib胶囊/片剂获批临床，拟定适应症为：tuvusertib联合尼拉帕利或lartesertib治疗在既往PARP抑制剂治疗期间疾病进展的BRCA突变和/或同源重组缺陷（HRD）阳性卵巢上皮癌患者。公开资料显示，tuvusertib是一款ATR抑制剂，lartesertib (M4076)是一款ATM抑制剂。研究显示，在ATM缺失的肿瘤细胞中，ATR抑制剂可以产生合成致死效应，在导致ATM缺失肿瘤细胞死亡的同时，并不影响正常细胞。此外，ATR抑制剂还能与PARP抑制剂联合以增强治疗敏感性。在国际范围内，这款联合疗法已经进入2期临床研究阶段。除了上述产品，本周首次在中国获批IND的1类新药还包括：济煜医药申报的化药1类新药JMKX005425片获批临床，拟开发治疗微卫星高度不稳定型或错配修复缺陷型晚期实体瘤；维眸生物申报的1类新药VVN432鼻喷雾剂，拟开发治疗慢性鼻窦炎（CRS）；舶望制药申报的化药1类新药BW-40202注射液获批临床，拟用于治疗补体介导的肾病，包括免疫球蛋白A肾病（IgA肾病）等；云白药征武科技申报的化药1类新药JZ-14胶囊，拟开发治疗溃疡性结肠炎；英创医药科技有申报的1类新药IGP-14068-TM片获批临床，拟用于治疗晚期实体瘤（包括但不限于高级别浆液性卵巢癌和三阴性乳腺癌等）；微能生命科技申报的1类新药VPD/FC01002 注射液获批临床，拟开发治疗免疫重建不全等。期待这些在研新药后续临床研发进程顺利，早日为患者带来新的治疗选择。参考资料：[1]中国国家药监局药品审评中心（CDE）官网. Retrieved Jun 14, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]各公司官网及公开资料版权说明：本文欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

抗体药物偶联物申请上市临床3期临床2期临床1期

2025-04-29

·Endpoints

Artios drug exploits ‘replication stress’ in cancer, shrinking subset of tumors in early study

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

临床结果临床3期临床2期

100 项与 Tuvusertib 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
复发性子宫内膜癌	临床2期	美国	EMD Serono, Inc.	2024-11-14
HRD 阳性卵巢癌	临床2期	美国	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	澳大利亚	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	比利时	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	丹麦	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	法国	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	德国	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	以色列	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	意大利	EMD Serono Research & Development Institute, Inc.	2024-10-30
HRD 阳性卵巢癌	临床2期	荷兰	EMD Serono Research & Development Institute, Inc.	2024-10-30

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05947500 (MATRiX, SITC2025)	临床2期	梅克尔细胞癌	24	Tuvusertib	遞窪鑰選鬱鑰艱選糧蓋(簾蓋鏇顧鏇願鏇獵憲觸) = 壓糧廠醖繭艱糧簾淵廠衊糧構繭鹽繭淵淵願鑰 (夢衊範網鏇願夢夢範窪 )	积极	2025-11-05
NCT05947500 (MATRiX, SITC2025)	临床2期	梅克尔细胞癌	24	Tuvusertib + Avelumab	遞窪鑰選鬱鑰艱選糧蓋(簾蓋鏇顧鏇願鏇獵憲觸) = 鬱遞鏇獵膚醖衊鑰蓋顧衊糧構繭鹽繭淵淵願鑰 (夢衊範網鏇願夢夢範窪 )	积极	2025-11-05
NCT05986071 (MATRIx, ESMO2025)	临床1/2期	ER positive \| HER2 negative	45	Tuvusertib 130 mg QD500 mg fulvestrantQD + Tuvusertib 130 mg QD500 mg fulvestrant	憲顧遞願齋簾範糧築壓(構齋襯網鹹壓淵襯齋製) = The most common treatment-related AEs were low white blood cell count (30%, grade 1/2) and loss of appetite (13%, grade 1 only). 壓淵鬱艱壓獵醖鹹積積 (積膚觸觸衊構鏇簾鹽醖 )	积极	2025-10-17
NCT05986071 (MATRIx, ESMO2025)	临床1/2期	ER positive \| HER2 negative	45	Tuvusertib 180 mg QD500 mg fulvestrantQD + Tuvusertib 180 mg QD500 mg fulvestrant		积极	2025-10-17
NCT04170153 (NCT04170153, EANO2024)	临床1期	IDH1突变胶质瘤 P53 \| ATRX	5	Tuvusertib 180 mg QD	淵網獵淵選鹽醖壓齋觸(鏇壓蓋構蓋窪範顧鏇壓) = 鑰廠積鬱廠鑰構遞蓋廠醖憲窪構廠網繭顧膚觸 (選獵選製鏇餘網壓顧鑰 ) 更多	积极	2024-10-17
NCT05396833 (DDRiver Solid Tumors 320, ASCO2024) 人工标引	临床1期	实体瘤	22	tuvusertib+avelumab	糧獵獵衊衊襯顧蓋衊鏇(鏇簾廠艱觸襯鏇獵願繭) = 積醖構膚淵膚齋網壓遞繭構齋膚壓簾顧艱遞獵 (簾遞繭願簾繭鏇願積醖 ) 更多	积极	2024-05-24
NCT05396833 (DDRiver Solid Tumors 320, ASCO2024) 人工标引	临床1期	实体瘤	-	tuvusertib+lartesertib	觸醖網淵鏇鬱築壓簾鑰(遞獵顧簾襯獵襯顧構鏇) = No target inhibition was seen for tuvusertib at 90 mg QD and lartesertib at 50 mg QD 齋壓鏇夢構築遞齋構築 (簾襯築繭夢鹽選窪鬱齋 ) 更多	积极	2024-05-24
NCT04170153 (DDRiver Solid Tumors 301, ASCO2024) 人工标引	临床1期	实体瘤 BRCA Gene Mutation Negative \| HRD Positive \| HER2 Negative \| ... 更多	43	Tuvusertib 180 mg QD and Niraparib 100 mg QD	遞願構遞鑰襯網糧襯獵(簾廠簾鹽窪艱選願膚廠) = 構網鑰獵壓壓醖醖網製膚鑰衊獵遞觸廠範鬱鹹 (鬱鬱糧築膚餘憲願壓壓 ) 更多	积极	2024-05-24
NCT04170153 (DDRiver Solid Tumours 301, ESMO2022) 人工标引	临床1期	肿瘤 ARID1A \| ATM \| ATRX ... 更多	55	M1774 (5-80 mg QD)	築簾醖構網餘壓齋網鬱(鹹齋襯鏇製築醖鑰餘憲) = 窪積鬱窪餘蓋選壓憲窪壓憲憲繭積膚範醖鬱製 (艱繭糧製餘鹽憲範選選 )	积极	2022-09-12
NCT04170153 (DDRiver Solid Tumours 301, ESMO2022) 人工标引	临床1期	肿瘤 ARID1A \| ATM \| ATRX ... 更多	55	M1774 (130 mg QD)	築簾醖構網餘壓齋網鬱(鹹齋襯鏇製築醖鑰餘憲) = 願鏇獵鹹簾獵網餘網夢壓憲憲繭積膚範醖鬱製 (艱繭糧製餘鹽憲範選選 )	积极	2022-09-12